EZH2 inhibition and 5-azacytidine enhance antitumor immunity in PTEN-deficient glioblastoma by activation viral mimicry response.

in Journal for immunotherapy of cancer by Dandan Zhu, Zeying Li, Huolun Feng, Jiabin Zheng, Xiao Xiao, Zuda Huang, Liangying Zheng, Jieqing Guo, Fa Ling, Yong Li, Fan Xing

TLDR

  • The study identified a new therapeutic strategy for patients with PTEN-deficient glioblastoma (GBM) by reactivating the endogenous retrovirus (ERV)-MAVS-IFN pathway, which enhances antitumor immunity and improves outcomes.
  • The combination of 5-azacytidine and EZH2 inhibition restored robust type I interferon signaling, promoted ERV transcriptional activation, and reprogrammed the tumor microenvironment to boost antitumor immunity.

Abstract

PTEN-deficient glioblastoma (GBM) is characterized by an immunosuppressive tumor microenvironment (TME), therapeutic resistance, and poor prognosis. Emerging evidence suggests that dysregulation of the endogenous retrovirus (ERV)-MAVS-IFN pathway may contribute to immune evasion in cancer, but its role in PTEN-deficient GBM remains unclear. Using flow cytometry and single-cell RNA sequencing, we analyzed the immune landscape of PTEN-deficient GBM. We evaluated the effects of 5-azacytidine (5-AZA) monotherapy and its combination with EZH2 inhibition (EZH2i) on ERV reactivation, type I interferon (IFN) responses, and TME remodeling. Mechanistic studies focused on H3K27me3-mediated epigenetic regulation of ERV expression. We found that PTEN deficiency suppresses type I IFN responses by impairing viral mimicry through dysregulation of the ERV-MAVS-IFN pathway, thereby sustaining an immunosuppressive TME. While 5-AZA alone failed to reactivate ERVs or overcome therapeutic resistance, combining it with EZH2i synergistically restored robust type I IFN signaling. This combination therapy reduced H3K27me3 levels, promoting ERV transcriptional activation and enhancing 5-AZA-induced viral mimicry. Consequently, the dual treatment reprogrammed the TME to boost antitumor immunity and suppress tumor progression. Our study demonstrates that PTEN-deficient GBM evades immune surveillance by suppressing the ERV-MAVS-IFN axis. The combination of EZH2i and 5-AZA overcomes this resistance by epigenetically reactivating viral mimicry, offering a promising therapeutic strategy to enhance antitumor immunity and improve outcomes in patients with PTEN-deficient GBM.

Overview

  • The study focused on understanding the role of the endogenous retrovirus (ERV)-MAVS-IFN pathway in PTEN-deficient glioblastoma (GBM) and the potential therapeutic benefits of reactivating this pathway.
  • The researchers used flow cytometry and single-cell RNA sequencing to analyze the immune landscape of PTEN-deficient GBM and evaluated the effects of 5-azacytidine (5-AZA) monotherapy and its combination with EZH2 inhibition on ERV reactivation, type I interferon (IFN) responses, and tumor microenvironment (TME) remodeling.
  • The primary objective of the study was to identify a therapeutic strategy to overcome the immunosuppressive TME and enhance antitumor immunity in patients with PTEN-deficient GBM.

Comparative Analysis & Findings

  • The study found that PTEN deficiency suppresses type I IFN responses by impairing viral mimicry through dysregulation of the ERV-MAVS-IFN pathway, thereby sustaining an immunosuppressive TME.
  • Combining 5-AZA with EZH2 inhibition synergistically restored robust type I IFN signaling, and reduced H3K27me3 levels, promoting ERV transcriptional activation and enhancing 5-AZA-induced viral mimicry.
  • The dual treatment reprogrammed the TME to boost antitumor immunity and suppress tumor progression, offering a promising therapeutic strategy to enhance antitumor immunity and improve outcomes in patients with PTEN-deficient GBM.

Implications and Future Directions

  • The study demonstrates that PTEN-deficient GBM evades immune surveillance by suppressing the ERV-MAVS-IFN axis, highlighting the potential therapeutic benefits of targeting this pathway for cancer treatment.
  • Future studies should investigate the efficacy and safety of the combination therapy in clinical trials and explore its potential application in other cancer types.
  • Further research is needed to understand the underlying mechanisms of ERV reactivation and its effects on TME remodeling in GBM, which may lead to the development of novel therapeutic strategies.
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